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Early endpoints of a randomized phase II trial of preoperative chemotherapy with S-1/CDDP with or without trastuzumab followed by surgery for HER2-positive resectable gastric or esophagogastric junction adenocarcinoma with extensive lymph node metastasis: Japan Clinical Oncology Group study JCOG1301C (Trigger Study)

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Abstract

Background

This randomized phase II study explored the superiority of trastuzumab plus S-1 plus cisplatin (SP) over SP alone as neoadjuvant chemotherapy (NAC) for HER2-positive resectable gastric cancer with extensive lymph node metastasis.

Methods

Eligible patients with HER2-positive gastric or esophagogastric junction cancer and extensive lymph node metastasis were randomized to receive three or four courses of preoperative chemotherapy with SP (arm A) or SP plus trastuzumab (arm B). Following gastrectomy, adjuvant chemotherapy with S-1 was administered for 1 year in both arms. The primary endpoint was overall survival, and the sample size was 130 patients in total. The trial is registered with the Japan Registry of Clinical Trials, jRCTs031180006.

Results

This report elucidates the early endpoints, including pathological findings and safety. The study was terminated early due to slow patient accruals. In total, 46 patients were allocated to arm A (n = 22) and arm B (n = 24). NAC was completed in 20 patients (91%) in arm A and 23 patients (96%) in arm B, with similar incidences of grade 3–4 hematological and non-hematological adverse events. Objective response rates were 50% in arm A and 84% in arm B (p = 0·065). %R0 resection rates were 91% and 92%, and pathological response rates (≥ grade 1b in Japanese classification) were 23% and 50% (p = 0·072) in resected patients, respectively.

Conclusions

Trastuzumab can be safely added to platinum-containing doublet chemotherapy as NAC, and it has the potential to contribute to higher antitumor activity against locally advanced, HER2-positive gastric or esophagogastric junction cancer with extensive nodal metastasis.

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Acknowledgements

The results of this trial were presented at the 2022 American Society of Clinical Oncology Gastrointestinal Cancers Symposium. The authors thank the patients, their families, and the investigators of the JCOG Stomach Cancer Study Group for their contribution to the study and the members of the JCOG Data Center and JCOG Operations Office for their support in data management and study coordination (Ms. Mayumi Hayakawa). In Japan, clinical trials involving off-label drug use cannot be conducted under the National Health Insurance System. As the perioperative use of trastuzumab for resectable gastric cancer has not been approved, this study was conducted under the Advanced Medical Care System of the Ministry of Health, Labor and Welfare, Japan, with which off-label use of the drug became possible and routine medical care costs were reimbursed by the National Health Insurance System. The authors are grateful to Chugai Pharmaceutical Co., LTD for providing trastuzumab. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Chugai Pharmaceutical Co. Ltd.

Funding

This study was supported in part by the National Cancer Center Research and Development Fund (26-A-4, 29-A-3, 2020-J-3, 2023-J-03) and by a grant from the Applied Research for Innovative Treatment of Cancer Project of Health and Labour Sciences Research Expenses for Commission (H26-40) and AMED under Grant Numbers JP16ck0106043 and JP19ck0106311. Trastuzumab for the patients of the test arm was supplied free of charge by Chugai Pharmaceutical Co., LTD.

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Authors and Affiliations

  1. Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-Ku, Tokyo, Japan

    Masanori Tokunaga

  2. Department of Gastroenterology, Kanagawa Cancer Center, Kanagawa, Japan

    Nozomu Machida

  3. Japan Clinical Oncology Group Data Center/Operations Office, National Cancer Center Hospital, Tokyo, Japan

    Junki Mizusawa & Haruhiko Fukuda

  4. Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Japan

    Seiji Ito

  5. Department of Gastroenterological Surgery, Niigata Cancer Center Hospital, Niigata, Japan

    Hiroshi Yabusaki

  6. Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan

    Motohiro Hirao

  7. Department of Gastroenterological Surgery, Shizuoka General Hospital, Shizuoka, Japan

    Masaya Watanabe

  8. Department of Surgery, Toyonaka Municipal Hospital, Toyonaka, Japan

    Hiroshi Imamura

  9. Department of Gastric Surgery, National Cancer Center Hospital East, Chiba, Japan

    Takahiro Kinoshita

  10. Department of Surgery, Kinki University Faculty of Medicine, Osaka, Japan

    Takushi Yasuda

  11. Department of Gastrointestinal Surgery, Hiroshima City North Medical Center Asa Citizens Hospital, Hiroshima, Japan

    Jun Hihara

  12. Gastric Surgery Division, National Cancer Center Hospital, Tokyo, Japan

    Takaki Yoshikawa

  13. Department of Oncology and General Medicine, IMSUT Hospital, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    Narikazu Boku

  14. Division of Gastric Surgery, Shizuoka Cancer Center, Nagaizumi, Japan

    Masanori Terashima

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  1. Masanori Tokunaga
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Correspondence to Masanori Tokunaga.

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Conflict of interest

M Tokunaga has received lecture fees from Johnson & Johnson, Intuitive Surgical, Medtronic, Olympus Medical Systems, Ono Pharmaceutical, Lilly Japan, and Daiichi Sankyo. N Machida has received lecture fees from Taiho Pharmaceutical, Bristol-Myers Squibb Japan, Ono Pharmaceutical, Daiichi Sankyo, Lilly Japan, Yakult Honsha, Takeda, MSD K.K, Chugai Pharma, Merck KGaA and has received research expenses from MSD, AstraZeneca, Amgen, Ono Pharmaceutical, Taiho Pharmaceutical, ALX Oncology, Bristol-Myers Squibb Japan. J Mizusawa has received honoraria from Taiho Pharmaceutical and Chugai Pharmaceutical; his spouse is an employee of Pfizer. S Ito has received lecture fees from Taiho Pharmaceutical and Otsuka and has received research expenses from Ono Pharmaceutical, AstraZeneca, and Merck. H Fukuda has received lecture fees from CMIC Co., Ltd, Chugai Pharmaceutical Co., Ltd., and Kyowa Kirin Co., Ltd. T Yoshikawa Lecture fees from Chugai, Taiho Pharmaceutical, Daiichi Sankyo, Ono Pharmaceutical, Medtronic, BMS, EA Pharma, Johnson and Johnson, Intuitive Surgical, Japan Blood Products Organization, Olympus, Lilly, and Novartis. N Boku has received lecture fees from Taiho Pharmaceutical, Bristol-Myers Squibb Japan, Ono Pharmaceutical, Daiichi Sankyo, and Lilly Japan and has received research expenses from Ono Pharmaceutical and Takeda Pharmaceutical. M Terashima has received lecture fees from Taiho Pharmaceutical, Chugai, Ono Pharmaceutical, Bristol Myers Squibb Japan, Yakult, Takeda, Lilly Japan, Pfizer, Daiichi Sankyo, Johnson and Johnson, Medtronic Japan, Intuitive Japan, and Olympus. All remaining authors declare no conflicts of interest.

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Tokunaga, M., Machida, N., Mizusawa, J. et al. Early endpoints of a randomized phase II trial of preoperative chemotherapy with S-1/CDDP with or without trastuzumab followed by surgery for HER2-positive resectable gastric or esophagogastric junction adenocarcinoma with extensive lymph node metastasis: Japan Clinical Oncology Group study JCOG1301C (Trigger Study). Gastric Cancer 27, 580–589 (2024). https://doi.org/10.1007/s10120-024-01467-9

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